| 1 | J. Physiol. (Lond.) 2010 Sep 588: 3349-54 |
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| PMID | 20530112 |
| Title | Significance of SGK1 in the regulation of neuronal function. |
| Abstract | The present brief review highlights the putative role of the serum- and glucocorticoid-inducible-kinase-1 (SGK1) in the regulation of neuronal function. SGK1 is genomically upregulated by cell shrinkage and by a variety of hormones including mineralocorticoids and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase (PI3-kinase), phosphoinositide-dependent kinase PDK1 and mammalian target of rapamycin mTORC2. SGK1 upregulates ion channels (e.g. SCN5A, ENaC, ASIC1, TRPV5,6, ROMK, Kv1.1-5, KCNEx/KCNQ1-5, GluR6, VSOAC, ClC2, CFTR), carriers (e.g. NHE3, NKCC2, NCC, NaPiIIb, SMIT, GLUT1,4, SGLT1, NaDC, EAAT1-5, SN1, ASCT2, 4F2/LAT, PepT2), and the Na(+)/K(+)-ATPase. SGK1 regulates enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g. forkhead transcription factor Foxo3a, ?-catenin, nuclear factor-kappa-B (NFB)). SGK1 participates in the regulation of transport, hormone release, neuroexcitability, inflammation, coagulation, cell proliferation and apoptosis. SGK1 contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Presumably, SGK1 contributes to the regulation of diverse cerebral functions (e.g. memory consolidation, fear retention) and the pathophysiology of several cerebral diseases (e.g. Parkinson's disease, schizophrenia, depression, Alzheimer's disease). Despite multiple SGK1 functions, the phenotype of the SGK1 knockout mouse is mild and becomes only apparent under challenging conditions. |
| SCZ Keywords | schizophrenia |
| 2 | JAMA Psychiatry 2015 Aug 72: 747-56 |
| PMID | 26038830 |
| Title | Altered Markers of Cortical ?-Aminobutyric Acid Neuronal Activity in Schizophrenia: Role of the NARP Gene. |
| Abstract | In schizophrenia, working memory deficits appear to reflect abnormalities in the generation of gamma oscillations in the dorsolateral prefrontal cortex. The generation of gamma oscillations requires the phasic excitation of inhibitory parvalbumin-containing interneurons. Thus, gamma oscillations depend, in part, on the number of synaptic glutamate receptors on parvalbumin interneurons. However, little is known about the molecular factors that regulate glutamate receptor-mediated excitation of parvalbumin interneurons in schizophrenia. To quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission. Postmortem brain specimens (n?=?206) were obtained from individuals with schizophrenia, bipolar disorder, or major depressive disorder and from well-matched healthy persons (controls). For a study of brain tissue, quantitative polymerase chain reaction, in situ hybridization, or microarray analyses were used to measure transcript levels in the dorsolateral prefrontal cortex at gray matter, laminar, and cellular levels of resolutions. This study was conducted between January 1, 2013, and November 30, 2014. Expression levels for NARP, ARC, and SGK1 messenger RNA (mRNA) were compared between specimens from individuals with schizophrenia and controls. Diagnostic specificity was assessed by quantifying NARP mRNA levels in specimens from individuals with mood disorders. By quantitative polymerase chain reaction, levels of NARP mRNA were significantly lower by 25.6% in specimens from individuals with schizophrenia compared with the controls (mean [SD], 0.036 [0.018] vs 0.049 [0.015]; F1,114?=?21.0; P?SGK1 (F1,110?=?2.52; P?=?.12) were not significant. These findings were supported by in situ hybridization (NARP; individuals with schizophrenia vs controls: 40.1% lower [P?=?.003]) and microarray analyses (NARP; individuals with schizophrenia vs controls: 12.2% lower in layer 3 [P?=?.11] and 14.6% lower in layer 5 pyramidal cells [P?=?.001]). In schizophrenia specimens, NARP mRNA levels were positively correlated with GAD67 mRNA (r?=?0.55; P?Given the role of NARP in the formation of excitatory inputs to parvalbumin (and perhaps somatostatin) interneurons, our findings suggest that lower NARP mRNA expression contributes to lower excitatory drive onto parvalbumin interneurons in schizophrenia. This reduced excitatory drive may lead to lower synthesis of ?-aminobutyric acid in these interneurons, contributing to a reduced capacity to generate the gamma oscillations required for working memory. |
| SCZ Keywords | schizophrenia |
| 3 | Biomed Res Int 2015 -1 2015: 492367 |
| PMID | 25705664 |
| Title | Disturbance of oligodendrocyte function plays a key role in the pathogenesis of schizophrenia and major depressive disorder. |
| Abstract | The major psychiatric disorders such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained upregulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (SGK1) mRNA expression in oligodendrocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought to be related to depressive-like symptoms. In this review, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD. |
| SCZ Keywords | schizophrenia |